Osanetant

Osanetant (developmental code name SR-142,801) is a neurokinin 3 receptor antagonist which was developed by Sanofi-Synthélabo and was being researched for the treatment of schizophrenia but was discontinued.[1][2] It was the first non-peptide NK3 antagonist developed in the mid-1990s.[3][4]

Osanetant
Clinical data
ATC code
  • none
Identifiers
  • N-(1-{3-[(3R)-1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl]propyl}-4-phenylpiperidin-4-yl]-N-methylacetamide
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
ECHA InfoCard100.233.307
Chemical and physical data
FormulaC35H41Cl2N3O2
Molar mass606.63 g·mol−1
3D model (JSmol)
  • CC(=O)N(C)C1(CCN(CC1)CCC[C@@]2(CCCN(C2)C(=O)C3=CC=CC=C3)C4=CC(=C(C=C4)Cl)Cl)C5=CC=CC=C5
  • InChI=1S/C35H41Cl2N3O2/c1-27(41)38(2)35(29-13-7-4-8-14-29)19-23-39(24-20-35)21-9-17-34(30-15-16-31(36)32(37)25-30)18-10-22-40(26-34)33(42)28-11-5-3-6-12-28/h3-8,11-16,25H,9-10,17-24,26H2,1-2H3/t34-/m0/s1 ☒N
  • Key:DZOJBGLFWINFBF-UMSFTDKQSA-N ☒N
 ☒NcheckY (what is this?)  (verify)

Professor David J. Anderson, Director and Leadership Chair of the Tianqiao and Chrissy Chen Institute for Neuroscience at California Institute of Technology, has advocated that osanetant be explored as a treatment for pain, anxiety, and aggression in humans and companion animals experiencing bereavement or social isolation, citing research suggesting that osanetant has an excellent safety profile and suppresses negative effects of social isolation in mice through an evolutionarily-conserved mechanism and without acting as a depressant.[5][6][7] Another potential application for osanetant is in the treatment of drug addiction, as it has been found to block the effects of cocaine in animal models.[8][9]

Osanetant is being investigated by Acer Therapeutics as a treatment for severe vasomotor symptoms such as a hot flashes and flushes among people experiencing menopause.[10]

Synthesis

Several different syntheses have been reported. Below are representative examples.

Synthesis (Glaxo):[11]

The reaction between 2-(3,4-Dichlorophenyl)-5-(tetrahydropyran-2-yloxy)pentanenitrile[12] (1) and methyl acrylate (2) gives 4-Cyano-4-(3,4-dichlorophenyl)-7-(oxan-2-yloxy)heptanoic aci [13] (3). Treatment with acid gives 3-[3-(3,4-Dichlorophenyl)-2,6-dioxopiperidin-3-yl]propyl acetate, CID:70104936 (4). Reduction of the imide with Borane dimethylsulfide afforded [182621-51-8] (5). The reaction of this intermediate with benzoyl chloride [98-88-4] gives CID:22741724 (6). Treatment with mesyl chloride completed the synthesis of CID:11812710 (7).

Synthesis (Warner Lambert):[14]

The reaction of 1-Benzyl-4-phenyl-4-piperidinol [63843-83-4] (1) with trimethylsilyl cyanide and subsequent Ritter reaction gave N-(1-Benzyl-4-phenylpiperidin-4-yl)formamide, CID:10979305 (2). The reduction of the formamide with lithium aluminium hydride gave 1-benzyl-N-methyl-4-phenylpiperidin-4-amine [172734-03-1] (3). Reaction with acetic anhydride gave CID:22741820 (4). Catalytic hydrogenation removal of the benzyl protecting group gave N-Methyl-N-(4-phenylpiperidin-4-yl)acetamide [172733-87-8] (5).

Convergent synthesis completes the synthesis of Osanetant.

CID:11119744
Osanetant precursor:[15]

Subsequent studies have shown that the Osanetant precursor is already a powerful BAT (biogenic amine transporter) agent without the need for having to surmount the total synthesis of Osanetant. The Ki numbers in the patent for Ex 58 are NET = 2.4nM & DAT = 13.8nM.

This is not the first time that Sanofi produced a 3-arylpiperidine having BAT dopaminergic properties. For example, 3-[3-(Trifluoromethyl)phenyl]piperidine [64321-45-5] was reported in a previous patent.[16] It was stated in the patent that such compounds can be expected to be able to treat depression, obesity, and Parkinson's disease.

References
  1. "osanetant Sanofi-Aventis discontinued, France". Highbeam. Archived from the original on 2016-03-11.
  2. Kamali F (July 2001). "Osanetant Sanofi-Synthélabo". Current Opinion in Investigational Drugs. 2 (7): 950–956. PMID 11757797.
  3. Emonds-Alt X, Bichon D, Ducoux JP, Heaulme M, Miloux B, Poncelet M, et al. (1995). "SR 142801, the first potent non-peptide antagonist of the tachykinin NK3 receptor". Life Sciences. 56 (1): PL27–PL32. doi:10.1016/0024-3205(94)00413-M. PMID 7830490.
  4. Quartara L, Altamura M (August 2006). "Tachykinin receptors antagonists: from research to clinic". Current Drug Targets. 7 (8): 975–992. doi:10.2174/138945006778019381. PMID 16918326. Archived from the original on 2011-07-25.
  5. Huberman A (2022-09-12). "Dr. David Anderson: The Biology of Aggression, Mating & Arousal". Huberman Lab. Retrieved 2022-10-23.
  6. Zelikowsky M, Hui M, Karigo T, Choe A, Yang B, Blanco MR, et al. (May 2018). "The Neuropeptide Tac2 Controls a Distributed Brain State Induced by Chronic Social Isolation Stress". Cell. 173 (5): 1265–1279.e19. doi:10.1016/j.cell.2018.03.037. PMC 5967263. PMID 29775595.
  7. "Osanetant - an overview | ScienceDirect Topics". www.sciencedirect.com. Retrieved 2022-11-24.
  8. De Souza Silva MA, Mello EL, Müller CP, Jocham G, Maior RS, Huston JP, et al. (May 2006). "The tachykinin NK3 receptor antagonist SR142801 blocks the behavioral effects of cocaine in marmoset monkeys". European Journal of Pharmacology. 536 (3): 269–278. doi:10.1016/j.ejphar.2006.03.010. PMID 16603151.
  9. Jocham G, Lezoch K, Müller CP, Kart-Teke E, Huston JP, de Souza Silva MA (September 2006). "Neurokinin receptor antagonism attenuates cocaine's behavioural activating effects yet potentiates its dopamine-enhancing action in the nucleus accumbens core". The European Journal of Neuroscience. 24 (6): 1721–1732. doi:10.1111/j.1460-9568.2006.05041.x. PMID 17004936. S2CID 29488484.
  10. Acer Therapeutics Inc. (2022-09-13). "A Phase 2A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study to Evaluate the Efficacy, Safety and Pharmacokinetics (PK) of ACER-801 for Treatment of Moderate to Severe Vasomotor Symptoms (VMS) Associated With Menopause". {{cite journal}}: Cite journal requires |journal= (help)
  11. Giardina GA, Grugni M, Rigolio R, Vassallo M, Erhard K, Farina C (October 1996). "A reliable and efficient synthesis of SR 142801". Bioorganic & Medicinal Chemistry Letters. 6 (19): 2307–2310. doi:10.1016/0960-894X(96)00419-2.
  12. "2-(3,4-Dichlorophenyl)-5-(tetrahydropyran-2-yloxy)pentanenitrile". PubChem. U.S. National Library of Medicine. CID:22376623.
  13. "4-Cyano-4-(3,4-dichlorophenyl)-7-(oxan-2-yloxy)heptanoic acid". PubChem. U.S. National Library of Medicine. CID:15381168.
  14. Chen HG, Chung FZ, Goel OP, Johnson D, Kesten S, Knobelsdorf J, Lee HT, Rubin JR (March 1997). "A practical and scalable synthesis of SR 142801, a tachykinin NK3 antagonist". Bioorganic & Medicinal Chemistry Letters. 7 (5): 555–560. doi:10.1016/S0960-894X(97)00064-4.
  15. Brown DG, Bernstein PR, Wu Y, Urbanek RA, Becker CW, Throner SR, et al. (January 2013). "Azepines and piperidines with dual norepinephrine dopamine uptake inhibition and antidepressant activity". ACS Medicinal Chemistry Letters. 4 (1): 46–51. doi:10.1021/ml300262e. PMC 4027539. PMID 24900562.
  16. Lucien Nedelec, Jacques Guillaume, & Claude Dumont, U.S. Patent 4,259,337 (1981 to Sanofi Aventis France).


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